U.S. patent application number 11/285961 was filed with the patent office on 2007-05-24 for atorvastatin formulation.
Invention is credited to Dafna Dlugatch, Zvika Doani.
Application Number | 20070116758 11/285961 |
Document ID | / |
Family ID | 36753965 |
Filed Date | 2007-05-24 |
United States Patent
Application |
20070116758 |
Kind Code |
A1 |
Dlugatch; Dafna ; et
al. |
May 24, 2007 |
Atorvastatin formulation
Abstract
Provided are atorvastatin compositions which reduce the effect
of food on the bioavailability of atorvastatin and methods for
making such compositions. Also provided are methods of reducing low
density lipoprotein by administering the compositions of the
invention.
Inventors: |
Dlugatch; Dafna; (Petach
Tikva, IL) ; Doani; Zvika; (Tel Mond, IL) |
Correspondence
Address: |
KENYON & KENYON LLP
ONE BROADWAY
NEW YORK
NY
10004
US
|
Family ID: |
36753965 |
Appl. No.: |
11/285961 |
Filed: |
November 23, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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60738828 |
Nov 21, 2005 |
|
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|
Current U.S.
Class: |
424/464 ;
514/423 |
Current CPC
Class: |
A61K 9/2059 20130101;
A61K 9/2013 20130101; A61P 3/06 20180101; A61K 31/4025 20130101;
A61K 9/2018 20130101; A61K 9/2866 20130101; A61K 9/2009 20130101;
A61K 31/401 20130101; A61K 9/2054 20130101; A61K 31/40 20130101;
A61K 9/2027 20130101 |
Class at
Publication: |
424/464 ;
514/423 |
International
Class: |
A61K 9/20 20060101
A61K009/20; A61K 31/401 20060101 A61K031/401 |
Claims
1. A pharmaceutical dosage form, which reduces food effect
encountered by administration of atorvastatin, comprising: (a) an
effective amount of atorvastatin; and (b) a pharmaceutically
acceptable excipient, wherein the dosage form exhibits a food
effect of less than about 45% as characterized by C.sub.max values,
and the atorvastatin contains at least one atorvastatin selected
from the group consisting of atorvastatin hemi-calcium Form V,
atorvastatin having an average particle size of at most about 50
microns, and micronized atorvastatin.
2. The pharmaceutical dosage form of claim 1 comprising at least
one atorvastatin selected from the group consisting of atorvastatin
hemi-calcium Form V and micronized atorvastatin.
3. The pharmaceutical dosage form of claim 1, wherein the dosage
form exhibits a food effect of less than about 30%.
4. The pharmaceutical dosage form of claim 1, wherein the dosage
form exhibits a food effect of less than about 20%.
5. The pharmaceutical dosage form of claim 1, wherein the dosage
form exhibits a C.sub.max-fed of at least about 20 ng/ml when dosed
at about 80 mg of atorvastatin.
6. The pharmaceutical dosage form of claim 1, wherein the dosage
form exhibits a C.sub.max-fed of at least about 30 ng/ml when dosed
at about 80 mg of atorvastatin.
7. The pharmaceutical dosage form of claim 1, wherein the dosage
form exhibits a C.sub.max-fed of at least about 40 ng/ml when dosed
at about 80 mg of atorvastatin.
8. The pharmaceutical dosage form of claim 1 comprising
atorvastatin hemi-calcium Form V.
9. The pharmaceutical dosage form of claim 1 comprising at least
one atorvastatin selected from the group consisting of atorvastatin
hemi-calcium Form V having an average particle size of at most
about 50 microns and micronized hemi-calcium Form V.
10. The pharmaceutical dosage form of claim 1 comprising
atorvastatin hemi-calcium Form VIII.
11. The pharmaceutical dosage form of claim 1 comprising at least
one atorvastatin selected from the group consisting of atorvastatin
hemi-calcium Form VIII having an average particle size of at most
about 50 microns and micronized hemi-calcium Form VIII.
12. The pharmaceutical dosage form of claim 1 comprising at least
one atorvastatin selected from the group consisting of atorvastatin
hemi-calcium ethanolate, atorvastatin hemi-calcium ipanolate, and
atorvastatin hemi-calcium hydrate.
13. The pharmaceutical dosage form of claim 1 comprising
atorvastatin having an average particle size of at most about 50
microns.
14. The pharmaceutical dosage form of claim 1 comprising
atorvastatin having an average particle size of at most about 20
microns.
15. The pharmaceutical dosage form of claim 1 comprising
atorvastatin having an average particle size of at most about 10
microns.
16. The pharmaceutical dosage form of claim 2 comprising micronized
atorvastatin having a particle size of at most about 50
microns.
17. The pharmaceutical dosage form of claim 2 comprising micronized
atorvastatin having a particle size of at most about 20
microns.
18. The pharmaceutical dosage form of claim 2 comprising micronized
atorvastatin having a particle size of at most about 10
microns.
19. The pharmaceutical dosage form of claim 2 comprising micronized
atorvastatin hemi-calcium Form V having a particle size of at most
about 50 microns.
20. The pharmaceutical dosage form of claim 2 comprising micronized
atorvastatin hemi-calcium Form VIII having a particle size of at
most about 50 microns.
21. The pharmaceutical dosage form of claim 1, wherein the
excipient is at least one member selected from the group consisting
of vitamin E, hydroxypropylcellulose, microcrystalline cellulose,
crospovidone, sodium bicarbonate, meglumine, polacrilin, calcium
phosphate, lactose, colloidal silicone dioxide, talc, magnesium
stearate, croscarmellose, sodium carbonate, polyplasdone, magnesium
aluminum silicate, sodium stearyl fumarate, and a coating.
22. The pharmaceutical dosage form of claim 1, wherein the
excipient is at least one member selected from the group consisting
of mannitol, crospovidone, polyvinylpyrrolidone, vitamin E, tris
hydroxymethylaminoethane, dibasic calcium phosphate anhydrous,
sodium stearyl fumarate, and a coating.
23. The pharmaceutical dosage form of claim 1, wherein the
excipient is at least one member selected from the group consisting
of calcium oxide, magnesium oxide, calcium magnesium carbonate,
carbonates or bicarbonates of sodium, potassium or ammonium;
ammonium or alkali metal salts of phosphoric acid or pyrophosphate;
ammonium or alkali metal salts of carboxylic acids or fatty acids;
calcium magnesium acetate, ammonium or alkali metal salts of
aspartic or glutamic acid; carbonates of lysine or arginine;
bicarbonates of lysine, arginine, cystine or histidine; free base
forms of lysine, arginine, tryptophan, histidine, asparagine or
glutamine; carboxylic acid salts of lysine, arginine or histidine;
salt forms of cystine, phenols, biophenols or flavonoids, vitamin
P, tyrosine, isoflavones, polymers carrying amine functions,
polymers carrying acid functions in their salt forms, polyvinyl
acetate or phthalate; and peptides or proteins with iso-electric
point greater than 4.5.
24. The pharmaceutical dosage form of claim 1 in an oral dosage
form.
25. The pharmaceutical dosage form of claim 1 in the form of a
tablet.
26. A method of preparing a pharmaceutical dosage form, which
reduces food effect encountered by administration of atorvastatin,
comprising the steps of: (a) preparing a mixture of atorvastatin
and at least one pharmaceutically acceptable excipient; and (b)
formulating the mixture into a dosage form, wherein the dosage form
exhibits a food effect of less than about 45% as characterized by
C.sub.max values, and the atorvastatin contains at least one
atorvastatin selected from the group consisting of atorvastatin
hemi-calcium Form V, atorvastatin having an average particle size
of at most about 50 microns, and micronized atorvastatin.
27. The method of claim 26, wherein the atorvastatin contains at
least one atorvastatin selected from the group consisting of
atorvastatin hemi-calcium Form V and micronized atorvastatin.
28. The method of claim 26, wherein the dosage form exhibits a
C.sub.max-fed of at least about 20 ng/ml when dosed at about 80 mg
of atorvastatin.
29. The method of claim 26, wherein the dosage form exhibits a
C.sub.max-fed of at least about 30 ng/ml when dosed at about 80 mg
of atorvastatin.
30. The method of claim 26, wherein the dosage form exhibits a
C.sub.max-fed of at least about 40 ng/ml when dosed at about 80 mg
of atorvastatin.
31. The method of claim 26, wherein the atorvastatin contains
atorvastatin hemi-calcium Form V.
32. The method of claim 26, wherein the atorvastatin contains
atorvastatin hemi-calcium Form VIII.
33. The method of claim 26, wherein the atorvastatin contains
atorvastatin having an average particle size of at most about 50
microns.
34. The method of claim 26, wherein the excipient is at least one
member selected from the group consisting of vitamin E,
hydroxypropylcellulose, microcrystalline cellulose, crospovidone,
sodium bicarbonate, meglumine, polacrilin, calcium phosphate,
lactose, colloidal silicone dioxide, talc, magnesium stearate,
croscarmellose, sodium carbonate, polyplasdone, magnesium aluminum
silicate, sodium stearyl fumarate, and a coating.
35. The method of claim 26, wherein the excipient is at least one
member selected from the group consisting of mannitol,
crospovidone, polyvinylpyrrolidone, vitamin E, tris
hydroxymethylaminoethane, dibasic calcium phosphate anhydrous,
sodium stearyl fumarate, and a coating.
36. The method of claim 26, wherein the excipient is at least one
member selected from the group consisting of calcium oxide,
magnesium oxide, calcium magnesium carbonate, carbonates or
bicarbonates of sodium, potassium or ammonium; ammonium or alkali
metal salts of phosphoric acid or pyrophosphate; ammonium or alkali
metal salts of carboxylic acids or fatty acids; calcium magnesium
acetate, ammonium or alkali metal salts of aspartic or glutamic
acid; carbonates of lysine or arginine; bicarbonates of lysine,
arginine, cystine or histidine; free base forms of lysine,
arginine, tryptophan, histidine, asparagine or glutamine;
carboxylic acid salts of lysine, arginine or histidine; salt forms
of cystine, phenols, biophenols or flavonoids, vitamin P, tyrosine,
isoflavones, polymers carrying amine functions, polymers carrying
acid functions in their salt forms, polyvinyl acetate or phthalate;
and peptides or proteins with iso-electric point greater than
4.5.
37. The method of claim 26, wherein the method comprises the steps
of: (a) preparing a mixture of atorvastatin and a pharmaceutically
acceptable excipient; (b) granulating the mixture to form granules;
and (c) formulating the granules into the dosage form.
38. The method of claim 26, wherein the method comprises the steps
of: (a) preparing a mixture of atorvastatin and at least one
pharmaceutically acceptable excipient; (b) preparing a solution
comprised of vitamin E and hydroxypropylcellulose; (c) granulating
the mixture with the solution to obtain granules; (d) combining at
least one of crospovidone or colloidal silicone dioxide with the
granules; and (e) adding at least one of magnesium stearate or talc
to form the dosage form.
39. The method of claim 38, further comprising adding to the
mixture of step (a) at least one member selected from the group
consisting of microcrystalline cellulose, crospovidone, sodium
bicarbonate, meglumine, polacrilin potassium, dibasic calcium
phosphate anhydrous, and lactose monohydrate.
40. The method of claim 26, wherein the mixture is formulated into
an oral dosage form.
41. The method of claim 26, wherein the mixture is compressed into
a tablet.
42. The method of claim 37, further comprising coating the
tablet.
43. The method of claim 26, wherein the method comprises the steps
of: (a) preparing a mixture of atorvastatin hemi-calcium,
microcrystalline cellulose, crospovidone, sodium bicarbonate,
meglumine, polacrilin potassium, dibasic calcium phosphate
anhydrous, and lactose monohydrate; (b) preparing a solution
comprised of vitamin E and hydroxypropylcellulose; (c) granulating
the mixture with the solution to obtain granules; (d) mixing
crospovidone and colloidal silicone dioxide with the granules; (e)
adding magnesium stearate and talc; (f) compressing the resulting
mixture into a tablet; and (g) coating the tablet to form the
dosage form.
44. A dosage form prepared according to the method of claim 26.
45. A dosage form prepared according to the method of claim 27.
46. A method of reducing low density lipoprotein comprising
administering the dosage form prepared according to the method of
claim 26 to a patient in need thereof.
47. A method of reducing low density lipoprotein comprising
administering the dosage form prepared according to the method of
claim 27 to a patient in need thereof.
48. A method of reducing low density lipoprotein comprising
administering the dosage form of claim 26 to a patient in need
thereof.
49. A method of reducing low density lipoprotein comprising
administering the dosage form of claim 27 to a patient in need
thereof.
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. provisional
application serial number AWAITED (attorney docket no. 1662/98401),
filed Nov. 21, 2005, the contents of which is incorporated herein
by reference.
FIELD OF THE INVENTION
[0002] The invention encompasses atorvastatin compositions which
reduce the effect of food on the bioavailability of atorvastatin,
methods for making such compositions, and a method of reducing low
density lipoprotein by administering the compositions of the
invention.
BACKGROUND OF THE INVENTION
[0003] Atorvastatin has the chemical name
[R--(R*,R*)]-2-(4-fluorophenyl)-.beta.,.delta.-dihydroxy-5-(1-methylethyl-
)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid
and is depicted below in lactone form in formula (I) and its
calcium salt of formula (II): ##STR1##
[0004] Atorvastatin is a member of the class of drugs called
statins. Statin drugs are apparently currently the most
therapeutically effective drugs available for reducing low density
lipoprotein (LDL) particle concentration in the blood stream of
subjects.
[0005] The mechanism of action of statin drugs has been elucidated
in some detail. Statins supposedly interfere with the synthesis of
cholesterol and other sterols in the liver by competitively
inhibiting the 3-hydroxy-3-methyl-glutaryl-coelizyme, a reductase
enzyme ("HMG-CoA reductase"). HMG-CoA reductase reportedly
catalyzes the conversion HMG to mevalonate, which is the rate
determining step in the biosynthesis of cholesterol.
[0006] Atorvastatin was supposedly disclosed in U.S. Pat. No.
4,681,893. Atorvastatin hemi-calcium salt trihydrate is marketed
under the name LIPITOR.RTM. by Pfizer, Inc.
[0007] In general, it is known that the absorption and
bioavailability of any particular therapeutic agent can be affected
by numerous factors when dosed orally. Such factors include the
presence of food in the gastrointestinal (GI) tract because, in
general, the gastric residence time of a drug is usually
significantly longer in the presence of food than in the fasted
state. If the bioavailability of a drug is affected beyond a
certain point due to the presence of food in the GI tract, the drug
is said to exhibit a "food effect."
[0008] Food effects are important inasmuch as, when a drug exhibits
an adverse food effect, there is risk associated with administering
it to a patient who has eaten recently. The risk derives from the
potential that absorption into the bloodstream may be adversely
affected to the point that the patient risks insufficient
absorption to remediate the condition for which the drug was
administered.
[0009] Atorvastatin is reported to have a very low absorption when
taken with food as compared to when it is ingested alone.
Therefore, one of the main challenges in the development of
atorvastatin formulations is the effect of food on the
bioavailability of atorvastatin. For example, bioavailability of
atorvastatin may apparently be reduced by as much as 70% when it is
ingested with food.
[0010] Therefore, there is a need for atorvastatin formulations and
methods of their preparation that effectively reduce the food
effect encountered by the administration of atorvastatin.
SUMMARY OF THE INVENTION
[0011] The present invention provides atorvastatin formulations
that effectively reduce the food effect associated with
administration of atorvastatin.
[0012] In one embodiment, the present invention encompasses a
pharmaceutical dosage form, which reduces food effect encountered
by the administration of atorvastatin, comprising an effective
amount of atorvastatin and a pharmaceutically acceptable excipient,
wherein the dosage form exhibits a food effect of less than about
45% as characterized by C.sub.max values, and the atorvastatin
contains at least one atorvastatin selected from the group
consisting of atorvastatin hemi-calcium Form V, atorvastatin having
an average particle size of at most about 50 microns, and
micronized atorvastatin.
[0013] In another embodiment, the present invention encompasses a
pharmaceutical dosage form, which reduces food effect encountered
by the administration of atorvastatin, comprising an effective
amount of atorvastatin and a pharmaceutically acceptable excipient,
wherein the dosage form exhibits a food effect of less than about
45% as characterized by C.sub.max values, and the atorvastatin
contains at least one atorvastatin selected from the group
consisting of atorvastatin hemi-calcium Form V and micronized
atorvastatin. Preferably, the micronized atorvastatin has a
particle size of at most about 20 microns, and more preferably at
most about 10 microns.
[0014] Preferably, the dosage form exhibits a food effect of less
than about 30%, and more preferably less than about 20% as measured
by C.sub.max values.
[0015] In a preferred embodiment, a dosage form of the invention
provides a C.sub.max-fed of at least about 20 ng/ml when dosed at
about 80 mg of atorvastatin. Preferably, the C.sub.max-fed is at
least about 30 ng/ml, and more preferably at least about 40 ng/ml
when dosed at about 80 mg of atorvastatin.
[0016] Preferably, the dosage form contains at least one of
atorvastatin hemi-calcium Form V, atorvastatin hemi-calcium Form
VIII having an average particle size of at most about 50 microns,
micronized hemi-calcium Form V, or micronized hemi-calcium Form
VIII. Also preferably, the dosage form contains at least one of
atorvastatin hemi-calcium ethanolate (containing up to 3% ethanol),
atorvastatin hemi-calcium ipanolate (containing up to 6%
iso-propanol), or atorvastatin hemi-calcium hydrate.
[0017] In another preferred embodiment, the dosage form contains
atorvastatin having an average particle size of at most about 20
microns, and more preferably, at most about 10 microns.
[0018] In one preferred embodiment, the excipient is at least one
member selected from the group consisting of vitamin E,
hydroxypropylcellulose, microcrystalline cellulose, crospovidone,
sodium bicarbonate, meglumine, polacrilin, calcium phosphate,
lactose, colloidal silicone dioxide, talc, magnesium stearate,
croscarmellose, sodium carbonate, polyplasdone, magnesium aluminum
silicate, sodium stearyl fumarate, and a coating.
[0019] In another preferred embodiment, the excipient is at least
one member selected from the group consisting of mannitol,
crospovidone, polyvinylpyrrolidone, vitamin E, tris
hydroxymethylaminoethane, dibasic calcium phosphate anhydrous,
sodium stearyl fumarate, and a coating.
[0020] In yet a further embodiment, the excipient is at least one
member selected from the group consisting of calcium oxide,
magnesium oxide, calcium magnesium carbonate, carbonates or
bicarbonates of sodium, potassium or ammonium; ammonium or alkali
metal salts of phosphoric acid or pyrophosphate; ammonium or alkali
metal salts of carboxylic acids or fatty acids; calcium magnesium
acetate, ammonium or alkali metal salts of aspartic or glutamic
acid; carbonates of lysine or arginine; bicarbonates of lysine,
arginine, cystine or histidine; free base forms of lysine,
arginine, tryptophan, histidine, asparagine or glutamine;
carboxylic acid salts of lysine, arginine or histidine; salt forms
of cystine, phenols, biophenols or flavonoids, vitamin P, tyrosine,
isoflavones, polymers carrying amine functions, polymers carrying
acid functions in their salt forms, polyvinyl acetate or phthalate;
and peptides or proteins with iso-electric point greater than
4.5.
[0021] Preferably, the dosage form is an oral dosage form, and more
preferably in the form of a tablet.
[0022] The present invention also encompasses methods of preparing
the dosage forms of the invention.
[0023] In one embodiment, the present invention encompasses a
method of preparing a pharmaceutical dosage form, which reduces
food effect encountered by the administration of atorvastatin,
comprising preparing a mixture of atorvastatin and a
pharmaceutically acceptable excipient, and formulating the mixture
into a dosage form, wherein the dosage form exhibits a food effect
of less than about 45% as characterized by C.sub.max values, and
the atorvastatin contains at least one atorvastatin selected from
the group consisting of atorvastatin hemi-calcium Form V,
atorvastatin having an average particle size of at most about 50
microns, and micronized atorvastatin.
[0024] In one embodiment, the present invention encompasses a
method of preparing a pharmaceutical dosage form, which reduces
food effect encountered by the administration of atorvastatin,
comprising preparing a mixture of atorvastatin and a
pharmaceutically acceptable excipient, and formulating the mixture
into a dosage form, wherein the dosage form exhibits a food effect
of less than about 45% as characterized by C.sub.max values, and
the atorvastatin contains at least one atorvastatin selected from
the group consisting of atorvastatin hemi-calcium Form V, and
micronized atorvastatin.
[0025] Preferably, the excipient is at least one member selected
from the group consisting of vitamin E, hydroxypropylcellulose,
microcrystalline cellulose, crospovidone, sodium bicarbonate,
meglumine, polacrilin, calcium phosphate, lactose, colloidal
silicone dioxide, talc, magnesium stearate, croscarmellose, sodium
carbonate, polyplasdone, magnesium aluminum silicate, sodium
stearyl fumarate, and a coating.
[0026] Also preferably, the excipient is at least one member
selected from the group consisting of mannitol, crospovidone,
polyvinylpyrrolidone, vitamin E, tris hydroxymethylaminoethane,
dibasic calcium phosphate anhydrous, sodium stearyl fumarate, and a
coating.
[0027] The excipient is also preferably at least one member
selected from the group consisting of calcium oxide, magnesium
oxide, calcium magnesium carbonate, carbonates or bicarbonates of
sodium, potassium or ammonium; ammonium or alkali metal salts of
phosphoric acid or pyrophosphate; ammonium or alkali metal salts of
carboxylic acids or fatty acids; calcium magnesium acetate,
ammonium or alkali metal salts of aspartic or glutamic acid;
carbonates of lysine or arginine; bicarbonates of lysine, arginine,
cystine or histidine; free base forms of lysine, arginine,
tryptophan, histidine, asparagine or glutamine; carboxylic acid
salts of lysine, arginine or histidine; salt forms of cystine,
phenols, biophenols or flavonoids, vitamin P, tyrosine,
isoflavones, polymers carrying amine functions, polymers carrying
acid functions in their salt forms, polyvinyl acetate or phthalate;
and peptides or proteins with iso-electric point greater than
4.5.
[0028] In a preferred embodiment, the method of preparing a
pharmaceutical dosage form, which reduces food effect encountered
by the administration of atorvastatin, comprises preparing a
mixture of atorvastatin and a pharmaceutically acceptable
excipient; granulating the mixture to form granules; and
formulating the granules into the dosage form.
[0029] In another preferred embodiment, the method of preparing a
pharmaceutical dosage form, which reduces food effect encountered
by the administration of atorvastatin, comprises preparing a
mixture of atorvastatin and at least one pharmaceutically
acceptable excipient; preparing a solution comprised of vitamin E
and hydroxypropylcellulose; granulating the solution with the
mixture to obtain granules; combining at least one of crospovidone
or colloidal silicone dioxide with the granules; and adding at
least one of magnesium stearate or talc to form the dosage form.
Preferably, at least one member selected from the group consisting
of microcrystalline cellulose, crospovidone, sodium bicarbonate,
meglumine, polacrilin potassium, dibasic calcium phosphate
anhydrous, and lactose monohydrate is added to the mixture with
atorvastatin before granulation.
[0030] In a more preferred embodiment, the method of preparing a
pharmaceutical dosage form, which reduces food effect encountered
by the administration of atorvastatin, comprises preparing a
mixture of atorvastatin hemi-calcium, microcrystalline cellulose,
crospovidone, sodium bicarbonate, meglumine, polacrilin potassium,
dibasic calcium phosphate anhydrous, and lactose monohydrate;
preparing a solution comprised of vitamin E and
hydroxypropylcellulose; granulating the solution with the mixture
to obtain granules; mixing crospovidone and colloidal silicone
dioxide with the granules; adding magnesium stearate and talc to
form a granulate mixture; compressing the granulate mixture into a
tablet; and coating the tablet to form the dosage form.
[0031] In a preferred embodiment, the dosage forms of the invention
are formulated into an oral dosage form, preferably in tablet form,
and more preferably in coated tablet form.
[0032] Another embodiment of the invention encompasses a method of
reducing low density lipoprotein by administering an effective
amount of the dosage forms of the invention to a patient in need
thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0033] The invention encompasses pharmaceutical dosage forms which
reduce the food effect encountered by the administration of
atorvastatin, methods for their preparation, and methods of
treatment using the same.
[0034] In one embodiment, the invention encompasses a
pharmaceutical dosage form, which reduces food effect encountered
by the administration of atorvastatin, comprising an effective
amount of atorvastatin and a pharmaceutically acceptable excipient,
wherein the dosage form exhibits a food effect as defined below of
less than about 45%. Preferably, the food effect is less than about
30%, and more preferably less than about 20%.
[0035] As used herein, a "food effect" occurs when the maximum
concentration in the blood plasma (C.sub.max) of a drug in a
subject is affected beyond a certain point due to the presence of
food in the GI tract.
[0036] A food effect can be detected and quantified as described,
for example, in Toothaker et al., ANN. REV. PHARMACOL. TOXICOL.,
vol. 20, 173-199, 1980, or in Welling et al., J. PHARM. SCI. vol.
68 (2), pp. 150-155, (1979). A food effect can be detected and
quantified as described, for example, by determining the area under
a curve (AUC), which plots the serum concentration (e.g., in
.mu.g/mL) of atorvastatin along the ordinate (Y-axis) against time
along the abscissa (X-axis). Generally, the values for AUC
represent a number of values taken from all the subjects in a
patient test population and are, therefore, mean values averaged
over the entire test population. By measuring the area under the
curve for a fed population of subjects (AUC.sub.fed) and comparing
it with the area for the same population of fasted subjects
(AUC.sub.fast), it can be determined whether a given drug exhibits
an adverse food effect or not. For example, food effect can be
determined as follows: Food
effect=AUC.sub.fast/AUC.sub.fed.times.100.
[0037] Food effect can also be measured by determining the peak
plasma concentration (C.sub.max) of atorvastatin for a population
of subjects. By determining the peak plasma concentration of
atorvastatin for a population of fasted subjects (C.sub.max-fast),
and comparing it with the peak plasma concentration of atorvastatin
for a population of fed subjects (C.sub.max-fed), it can be
determined whether a given drug exhibits an adverse food
effect.
[0038] According to this invention, food effect is determined as
follows: Food
effect=(C.sub.max-fast-C.sub.max-fed)/C.sub.max-fast.times.100
[0039] As used herein, a food effect is considered "reduced" if it
is less than about 45% as characterized by C.sub.max values.
[0040] In another embodiment, the dosage forms of the invention
provide a C.sub.max-fed of at least about 20 ng/ml when dosed at
about 80 mg of atorvastatin. Preferably, the C.sub.max-fed is at
least about 30 ng/ml when dosed at about 80 mg of atorvastatin, and
more preferably at least about 40 ng/when dosed at about 80 mg of
atorvastatin. One of ordinary skill in the art will appreciate that
C.sub.max values will vary with the dose administered.
[0041] As used herein, a "population of fed subjects" is one made
up of subjects each of whom has eaten a Food and Drug
Administration (FDA)-recommended standard high fat breakfast within
a period of twenty minutes, and then ingested (i.e., swallowed) the
test dosage form essentially immediately thereafter. A standard
high-fat breakfast consists of, for example, two eggs fried in one
tablespoon of butter, two strips of bacon, six ounces of hash brown
potatoes, two pieces of toast with two teaspoons of butter and two
pats of jelly, and eight ounces of whole milk. This standard
high-fat breakfast contains approximately 964 calories, 54%
supplied as fat (58 gm) and 12% supplied as protein, calculated
using the monograph "Nutritive Value of Foods," U.S. Department of
Agriculture Home and Garden Bulletin No. 72. Additional food can
also be consumed within the twenty minute period and the subject
still qualifies as "fed." A "fasted subject" for purposes of
definition and for measuring AUC.sub.fast is one who has not eaten
for at least ten hours, typically overnight, prior to ingestion of
the dosage form.
[0042] As used herein, the term "atorvastatin" includes
atorvastatin, any anhydrate, hydrates, solvates, salts and
equivalents thereof, and any crystalline or amorphous forms.
Atorvastatin hemi-calcium is preferred. Also preferred are hydrate,
ipanolate (containing up to 6% iso-propanol), and ethanolate
(containing up to 3% ethanol) forms of atorvastatin.
[0043] The atorvastatin used in the dosage forms of the invention
includes at least one of atorvastatin hemi-calcium Form V, or
atorvastatin having an average particle size of at most about 50
.mu.m. The atorvastatin used in the dosage forms of the invention
can also include micronized atorvastatin.
[0044] Crystalline atorvastatin hemi-calcium Form V is disclosed in
International Publication No. WO 01/36384, incorporated herein by
reference in its entirety. Crystalline atorvastatin hemi-calcium
Form VIII is disclosed in International Publication No. WO
02/43732, also incorporated herein by reference in its
entirety.
[0045] Preferably, dosage forms of the invention comprising
crystalline atorvastatin hemi-calcium Form V contain atorvastatin
hemi-calcium Form V in an amount of at least about 50% by weight of
the atorvastatin. The atorvastatin may be in micronized or
non-micronized form.
[0046] Also preferably, dosage forms of the invention comprising
crystalline atorvastatin hemi-calcium Form VIII contain
atorvastatin hemi-calcium Form VIII in an amount of at least about
50% by weight of the atorvastatin. Atorvastatin hemi-calcium Form
VIII is preferably in micronized form.
[0047] In a preferred embodiment, dosage forms of the invention
contain atorvastatin having an average particle size of at most
about 50 .mu.m when measured across the longest axis, preferably at
most about 20 .mu.m, and more preferably at most about 10 .mu.m. As
used herein, the term "average particle size" means that at least
50% of the particles in a sample have the specified size.
[0048] In another preferred embodiment, dosage forms of the
invention contain micronized atorvastatin. Generally, atorvastatin
in micronized form has significant pharmaceutical advantages. The
term "micronized atorvastatin" refers to atorvastatin having a
particle size distribution where at least about 90% of the
particles have a particle size of at most about 50 microns when
measured across the longest axis. Preferably, micronized
atorvastatin has a particle size of at most about 20 microns, and
more preferably at most about 10 microns.
[0049] Micronization may be a mechanical process that involves the
application of force to a particle, thereby resulting in the
break-up of the particle. Such force may be applied by collision of
particles at high speeds. Micronization may be carried out, for
example, by grinding, air-jet micronizer, Ball mill, or Pin mill to
produce micronized particles.
[0050] The size of a particle is determined by any of the methods
commonly known in the art. The following methods, for example, may
be used: sieves, sedimentation, electrozone sensing (coulter
counter), microscopy, or Low Angle Laser Light Scattering (LALLS).
The preferred methods for the present invention are the methods
most commonly used in the pharmaceutical industry, such as laser
diffraction or sieve analysis
[0051] The dosage form of the invention may contain any
pharmaceutically acceptable excipient known in the art.
[0052] In a preferred embodiment, the excipient is at least one of
vitamin E, hydroxypropylcellulose, microcrystalline cellulose,
crospovidone, sodium bicarbonate, meglumine, polacrilin including
polacrilin potassium, calcium phosphate such as dibasic calcium
phosphate anhydrous, lactose including the monohydrate, colloidal
silicone dioxide, talc, magnesium stearate, croscarmellose, sodium
carbonate, polyplasdone, magnesium aluminum silicate, sodium
stearyl fumarate, or a coating such as Opadry.
[0053] In another preferred embodiment, the excipient is at least
one of mannitol, crospovidone, polyvinylpyrrolidone, vitamin E,
tris hydroxymethylaminoethane, dibasic calcium phosphate anhydrous,
sodium stearyl fumarate, or a coating such as Opadry.
[0054] In a further embodiment, the excipient is at least one of
calcium oxide, magnesium oxide, calcium magnesium carbonate,
carbonates or bicarbonates of sodium, potassium or ammonium;
ammonium or alkali metal salts of phosphoric acid or pyrophosphate;
ammonium or alkali metal salts of carboxylic acids or fatty acids;
calcium magnesium acetate, ammonium or alkali metal salts of
aspartic or glutamic acid; carbonates of lysine or arginine;
bicarbonates of lysine, arginine, cystine or histidine; free base
forms of lysine, arginine, tryptophan, histidine, asparagine or
glutamine; carboxylic acid salts of lysine, arginine or histidine;
salt forms of cystine, phenols, biophenols or flavonoids, vitamin
P, tyrosine, isoflavones, polymers carrying amine functions,
polymers carrying acid functions in their salt forms, polyvinyl
acetate or phthalate; and peptides or proteins with iso-electric
point greater than 4.5.
[0055] The present invention also encompasses methods of preparing
the pharmaceutical dosage forms of the invention.
[0056] In one embodiment, the present invention encompasses a
method of preparing a pharmaceutical dosage form, which reduces the
food effect encountered by the administration of atorvastatin, by
preparing a mixture of atorvastatin and a pharmaceutically
acceptable excipient, and formulating the mixture into a dosage
form, wherein the dosage form exhibits a food effect of less than
about 45% as characterized by C.sub.max values.
[0057] The atorvastatin contains at least one of atorvastatin
hemi-calcium Form V atorvastatin having an average particle size of
at most about 50 microns, or micronized atorvastatin. In another
embodiment, the atorvastatin contains at least one of atorvastatin
hemi-calcium Form V or micronized atorvastatin.
[0058] In one embodiment, the method of preparing the
pharmaceutical dosage form of the invention includes preparing a
mixture of atorvastatin and at least one of vitamin E,
hydroxypropylcellulose, microcrystalline cellulose, crospovidone,
sodium bicarbonate, meglumine, polacrilin including polacrilin
potassium, calcium phosphate such as dibasic calcium phosphate
anhydrous, lactose including the monohydrate, colloidal silicone
dioxide, talc, magnesium stearate, croscarmellose, sodium
carbonate, polyplasdone, magnesium aluminum silicate, sodium
stearyl fumarate; and formulating the mixture into the dosage
form.
[0059] In another embodiment, the method of preparing the
pharmaceutical dosage form of the invention includes preparing a
mixture of atorvastatin and at least one of mannitol, crospovidone,
polyvinylpyrrolidone, vitamin E, tris hydroxymethylaminoethane,
dibasic calcium phosphate anhydrous, sodium stearyl fumarate; and
formulating the mixture into the dosage form.
[0060] One of ordinary skill in the art will appreciate that other
excipients such as those exemplified herein may also be added to
the mixture with atorvastatin.
[0061] Dosage forms of the invention may be prepared in accordance
with customary processing techniques for pharmaceutical
formulations wherein the ingredients are suitably processed and
formulated into a dosage form, e.g., compressed into a tablet, with
pharmaceutically acceptable excipients.
[0062] In a preferred embodiment, the method includes formulating
the dosage form into an oral dosage form, such as a tablet. More
preferably, the dosage form is formulated into a tablet and coated
with a coating, such as Opadry.
[0063] In one embodiment, the method of preparing the
pharmaceutical dosage form of the invention includes preparing a
mixture of atorvastatin and a pharmaceutically acceptable
excipient; granulating the mixture to form granules; and
formulating the granules into the dosage form.
[0064] The term "granulation" refers to processes where granules
are produced. Granulation may be carried out by any methods known
in the art.
[0065] In one embodiment, the method of preparing the
pharmaceutical dosage form of the invention includes preparing a
mixture of atorvastatin and at least one pharmaceutically
acceptable excipient; preparing a solution comprised of vitamin E
and hydroxypropylcellulose; granulating the solution with the
mixture to obtain granules; combining at least one of crospovidone
or colloidal silicone dioxide with the granules; and adding at
least one of magnesium stearate or talc to form the dosage
form.
[0066] In a preferred embodiment, at least one of microcrystalline
cellulose, crospovidone, sodium bicarbonate, meglumine, polacrilin,
calcium phosphate, or lactose added into the mixture with
atorvastatin before granulation. Preferably, all the ingredients
are added into the mixture before granulation, and more preferably,
in the order of atorvastatin calcium, microcrystalline cellulose,
crospovidone, sodium bicarbonate, meglumine, polacrilin, calcium
phosphate, and lactose.
[0067] In a more preferred embodiment, the present invention
encompasses a method of preparing a pharmaceutical dosage form,
which reduces the food effect encountered by the administration of
atorvastatin, by preparing a mixture of atorvastatin and at least
one of microcrystalline cellulose, crospovidone, sodium
bicarbonate, meglumine, polacrilin potassium, dibasic calcium
phosphate anhydrous, and lactose monohydrate; preparing a solution
comprised of vitamin E and hydroxypropylcellulose; granulating the
solution with the mixture to obtain granules; mixing crospovidone
and colloidal silicone dioxide with the granules; adding magnesium
stearate and talc to form a granulate mixture; compressing the
granulate mixture into a tablet; and coating the tablet to form the
dosage form.
[0068] Another embodiment of the invention encompasses a method of
reducing low density lipoprotein by administering an effective
amount of the dosage forms of the invention to a patient in need
thereof.
[0069] As used herein, "effective amount" means an amount of
atorvastatin that, when administered to a patient for treating a
disease or other undesirable medical condition, is sufficient to
have a beneficial effect with respect to that disease or condition.
The "effective amount" will vary depending on the disease or
condition and its severity, and the age, weight, etc., of the
patient to be treated. Determining the effective amount of
atorvastatin is within the ordinary skill of the art and requires
no more than routine experimentation.
[0070] In a preferred embodiment, atorvastatin is present in an
amount of from about 5% to about 20%, more preferably from about 5%
to about 10%, and more preferably in an amount of about 8%
[0071] Preferred unit dosages of the pharmaceutical compositions of
this invention typically contain from 0.5 to 100 mg of
atorvastatin. More usually, the atorvastatin is present in a unit
dosage in an amount of from 2.5 mg to 80 mg.
[0072] Dosage forms contemplated by the present invention may
include diluents, such as cellulose-derived materials like powdered
cellulose, microcrystalline cellulose, microfine cellulose, methyl
cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl
cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose
salts and other substituted and unsubstituted celluloses; starch;
pregelatinized starch; inorganic diluents like calcium carbonate
and calcium diphosphate and other diluents known to the
pharmaceutical industry. Yet other suitable diluents include waxes,
sugars and sugar alcohols like mannitol and sorbitol, acrylate
polymers and copolymers, as well as pectin, dextrin and
gelatin.
[0073] Further excipients that are within the contemplation of the
present invention include binders, such as acacia gum,
pregelatinized starch, sodium alginate, glucose and other binders
used in wet and dry granulation and direct compression tableting
processes. Excipients may further include disintegrants like sodium
starch glycolate, crospovidone, low-substituted hydroxypropyl
cellulose and others. In addition, excipients may include tableting
lubricants like magnesium and calcium stearate and sodium stearyl
fumarate; flavorings; sweeteners; preservatives; pharmacy
parenteral (including subcutaneous, intramuscular, and
intravenous), inhalant and ophthalmic administration. Although the
most suitable route in any given case will depend on the nature and
severity of the condition being treated, the most preferred route
of the present invention is oral. Dosages may be conveniently
presented in unit dosage form and prepared by any of the methods
well-known in the art of pharmacy.
[0074] Dosage forms include solid dosage forms, like tablets,
powders, capsules, suppositories, sachets, troches and losenges as
well as liquid suspensions and elixirs.
[0075] Capsule dosages may be made of gelatin or other conventional
encapsulating material. Tablets and powders may be coated. Tablets
and powders may be coated with an enteric coating. The enteric
coated powder forms may have coatings comprising phthalic acid
cellulose acetate, hydroxypropylmethyl-cellulose phthalate,
polyvinyl alcohol phthalate, carboxymethylethylcellulose, a
copolymer of styrene and maleic acid, a copolymer of methacrylic
acid and methyl methacrylate, and like materials, and if desired,
they may be employed with suitable plasticizers and/or extending
agents. A coated tablet may have a coating on the surface of the
tablet or may be a tablet comprising a powder or granules with an
enteric-coating.
[0076] Having described the invention with reference to certain
preferred embodiments, other embodiments will become apparent to
one skilled in the art from consideration of the specification. The
invention is further defined by reference to the following examples
describing in detail the preparation of the composition and methods
of use of the invention. It will be apparent to those skilled in
the art that many modifications, both to materials and methods, may
be practiced without departing from the scope of the invention.
EXAMPLES
Preparation of Atorvastatin Formulation in Example 9
[0077] Granulation Solution--Vitamin E (TPGS) and
hydroxypropylcellulose were dissolved into 95% ethanol.
[0078] Part I--The following materials were transferred into a
Diosna high shear mixer in the following order: lactose
monohydrate, croscarmellose sodium, atorvastatin hemi-calcium,
meglumine sodium bicarbonate, dibasic calcium phosphate anhydrous,
magnesium aluminum metasilicate, polacrilin potassium, and
microcrystalline cellulose. The material was mixed for 3 minutes,
and dry granulated in a Glatt GPCG-15 fluid bed dryer until it
reached 2.2% loss on drying. The resulting granules were sized
through an oscillating granulator (Frewitt) equipped with 0.8 mm
screen set at medium speed, and transferred into a dry blender.
[0079] Part II--Crospovidone was mixed with the granules for 10
minutes.
[0080] Part III--talc and magnesium stearate were added and mixed
for 5 minutes, and the material was then compressed into 963 mg
tablets.
[0081] The tablets were coated with a suspension of Opadry YS 1R
7003H white in purified water to form coated tablets under the
following conditions: inlet air temperature 55-65.degree. C.,
outlet air temperature 38-44.degree. C., spray rate 15-25 g/min,
for a batch size of 2500 tablets.
[0082] Examples 1-8, 10 and 11 can be similarly prepared.
Atorvastatin Formulation Bioavailability Results
[0083] The following table illustrates the compositions and
bioavailabilities of atorvastatin formulations prepared in Examples
1-11. TABLE-US-00001 TABLE 1 Atorvastatin formulations and
bioavailability data for Examples 1-11 Example 1 2 3 4 5 6 7 8 9 10
11 # of subjects 24 24 18 18 18 19 19 19 12 12 12 Fast Cmax
(ng/ml/hr) 67.9 49.9 42.5 50.42 41.5 41.62 45.36 40.26 38.73 55.17
25.45 Food Cmax (ng/ml/hr) 20.7 16.5 21.17 19.34 18.64 20.85 20.6
21.35 26.24 37.17 19.9 Food effect (%) 69.5 66.9 50.3 61.6 55 49.9
54.6 47 32.2 32.6 21.8 Ingredient Percent Composition (w/w) PART I
Lactose mono. 100 16.8 73.1 6.5 54.8 6.5 6.5 6.5 Mannitol 17.2 32.6
76 70.5 Croscarmellos Na. 4.1 8.7 4.2 8.7 8.7 8.7 Starch 1500 LM
15.9 Atorvastatin 9 7.7 8.4 8.4 6.9 8.4 8.4 8.4 8.4 8.4 Meglumine
12.2 12.2 12.2 12.2 Entery coat citric Acid 18.3 Na. Be Carbonate
18.3 18.3 18.3 18.3 Eudragit E PO 1.2 1 Di. Ba. Ca. Phosph. 8.8 8.8
8.8 8.8 5 Ca.cndot.Sulphate2 .times. H.sub.2O 36.1
Mag.cndot.Alum.cndot.Silicate 2.4 1.5 1.5 Polacrilin Potassium 4.1
4.2 7.1 4.2 4.2 4.2 Avicel 101/102/112 22.5 15.2 15.2 13.7 13.7 PVP
K-30 3.3 2.7 3.3 3.2 GRANULATION SOLUTION Polysorbate 80 2 3.3
Vitamine E TPGS 2.4 2.4 2 2.4 2.4 2.4 2.4 2.4
Klucel(hydroxypropylcellulose) 3.2 2.3 2.9 2.9 2.9 2.9 Tris
Hydroxymethylaminoethane 1 PART II Polyplasdone XL 4.1
CrospovidoneNF 8.7 3.7 8.2 8.2 8.2 8.2 4 CrospovidoneX L-10 9.6
PART III Na Stear. Fumarate 2.6 0.9 1 1.1 1 1 Talc 0.4 0.4 0.4 0.4
Mg. Stearate 1.2 1.2 1.2 1.2 COATING Opadry 2.5 3.7 2.4 2.4 2 2.4
2.4 2.4 2.4 2.9 AUC fast (ng/ml/hr) 124.9 103.9 121.4 107.8 98.95
119 113 116 150.9 180.8 141.5 AUC fed (ng/ml/hr) 174.9 144.7 149.1
150.7 142.4 157.6 165.8 146 143.5 150.5 131.7 Disintegration Time
0:06:21 0:01:42 0:04:50 0:07:43 0:03:59 0:05:58 0:05:29 0:04:37
0:05:53 0:17:10 0:15:58
[0084] Formulations in Examples 1-8 contain non-micronized
API-grade atorvastatin hemi-calcium Form VIII. The formulation in
Example 9 contains API-grade atorvastatin hemi-calcium Form VIII
micronized by air jet mill. The micronized atorvastatin product
contains 90% particles having a particle size of less than 10
microns, and 50% of particles less than 6 microns.
[0085] The formulation in Example 10 contains micronized API-grade
atorvastatin hemi-calcium Form V. The formulation in Example 11
contains non-micronized API-grade atorvastatin hemi-calcium Form
V.
[0086] As shown in Table 1, the food effect associated with
administration of atorvastatin in the fed state is reduced using
dosage forms of the invention illustrated in Examples 9, 10 and
11.
[0087] Subjects are fasted for 10 hours (overnight) at a dose of 80
mg. The average AUC for 12 to 18 volunteers in the fed state taking
the dosage forms of the invention is greater compared to the
average AUC for those taking the Lipitor.RTM. formulation in the
fed state.
Atorvastatin Formulation Dissolution Results
[0088] The following table contains dissolution data for Examples
1-11 obtained using the Paddle method (USP type II) at 50 RPM and
water, 900 ml at 37.degree. C., as the dissolution medium.
TABLE-US-00002 Example 1 2 3 4 6 7 8 9 10 11 % dissol. 15 45 22 22
44 32 32 38 22 15 in H.sub.2O, 5 min % dissol. 40 55 63 65 76 81 79
92 69 47 in H.sub.2O, 15 min % dissol. 85 60 79 90 83 100 89 99 97
65 In H.sub.2O, 30 min
* * * * *